Project Summary/Abstract For proper assembly of neuronal circuitry, axons have to be guided toward the correct targets and dendrites need to have the correct branching pattern and structural specialization. Despite considerable recent progress, much less is known about molecular mechanisms that control dendrite development as compared to those controlling axon guidance. About 15 years ago, our lab initiated a fruitful genetic dissection of dendrite development using Drosophila dendritic arborization (da) neurons as a model system. Multiple genetic screens and the ensuing analysis of dendrite mutants have yielded important insights about the molecular basis of dendrite development in Drosophila, including how axons and dendrites are made differently, how a neuron acquires its neuronal type specific morphology, how the dendrites of different neurons are organized relative to one another, how the size of a dendritic arbor is controlled, and how the pruning and remodeling of dendrites are regulated during development. Many of the molecular mechanisms controlling dendrite development have turned out to be conserved between Drosophila and mammals. Given that defects in dendrites are strongly associated with diseases such as Down syndrome and a subset of autism spectrum disorder, elucidating molecular pathways that control dendritic morphogenesis is not only of great interest in basic neuroscience but also important for the potential relevance to neurological disorders. As we continue to investigate the mechanisms that control dendrite morphogenesis, the knowledge we have gained provide a solid foundation for exploring some very interesting and understudied areas about dendrites: (1) The function of dendrites and the relationship between form and function. Drosophila da neurons are sensory neurons; all of them are mechano-sensitive. This has led us to venture into the study of mechano-sensation, the least well understood among our senses. Very few molecules have been firmly established as mechano-transduction channels. By using da neurons, we discovered that NompC is a bona fide mechano-transduction channel that enables the fly to sense gentle touch. We have also provided strong evidence that NompC is gated mechanically by a tethering mechanism that involves the Ankyrin repeats of NompC functioning as a gating spring. We propose to continue the in depth study of how NompC transduces force. Furthermore, because there are still many novel mechano-sensitive channels that remain to be discovered, we will use the fly sensory neuron as a model system to identify and study them. (2) Dendrite regeneration after injury. By using da neurons that are well suited for studying both axon regeneration and dendrite regeneration, we have been able to identify novel regulators of axon regeneration. Compare to axon regeneration, much less is known about dendrite regeneration (a recent PubMed search revealed over 1400 papers on axon regeneration but only 4 on dendrite regeneration to date). We are keen about uncovering mechanisms that control dendrite regeneration, an important but so far little studied problem.